Obesity Research Takes Aim at Protein Regulators

You are what you eat, but researchers are beginning to realize that what and when you eat is controlled by a myriad of underlying biological triggers acting in concert. When you feel hungry, when you feel satiated, how much you eat and how little you eat all could be controlled by factors hidden far from the look, smell and taste of good food.

The latest indication of this comes from work by a team of researchers at Tufts University, Boston, which has identified a protein in the brain that helps regulate food intake and body weight.

The work has implications for obesity and associated medical complications, including type 2 diabetes, said Maribel Rios, an associate professor of neuroscience at Tufts and the leader of the group. Rios’s team has discovered that a protein called alpha2/delta-1 influences the function of another protein called brain-derived neurotrophic factor (BDNF).

“We know that low levels of the BDNF protein in the brain lead to overeating and dramatic obesity in mice,” Rios said. “Deficiencies in BDNF have also been linked to obesity in humans. Now, we have discovered that the alpha2/delta-1 protein is necessary for normal BDNF function, giving us a potential new target for novel obesity treatments.”

The most recent work of the Rios group, “Hypothalamic dysfunction of the thrombospondin receptor alpha2/delta-1 underlies the overeating and obesity triggered by BDNF deficiency,” was published in the Jan. 8 issue of The Journal of Neuroscience.

“More than a quarter of the American population has been estimated to have an alteration in the BDNF gene that impedes its normal function and that has been associated with obesity susceptibility,” Rios said. “Our work is delineating the pathways connected to BDNF that control feeding behavior in an effort to define potential targets for intervention therapies for obese individuals. This is an important area of research considering the high prevalence of obesity and its associated medical complications, including type 2 diabetes.”

The BDNF protein and its effects on eating, anxiety and depression have been of particular interest to Rios, who has studied it for the past 17 years dating back to her postdoctoral days at the Whitehead Institute, in Cambridge, Massachusetts. In the most recent studies, Rios and her team performed a series of in vivo tests on mice.

When the team inhibited the alpha2/delta-1 protein in normal mice, mice ate significantly more food and gained weight. Conversely, when the team corrected the alpha 2/delta-1 deficiency in mice with reduced BDNF levels, overeating and weight gain were mitigated. In addition, blood sugar levels (related to diabetes in humans) were normalized.

“We blocked activity of the alpha2/delta-1 protein in mice using gabapentin,” said Joshua Cordeira, a graduate student working in the Rios lab and lead author of the study. “These mice ate 39 percent more food, and as a consequence gained substantially more weight than control mice over a seven-day period.”

“When we re-introduced alpha2/delta-1 in obese mice lacking BDNF in the brain, we saw a 15 to 20 percent reduction in food intake and a significant reduction in weight gain. Importantly, metabolic disturbances associated with obesity, including hyperglycemia and deficient glucose metabolism, were greatly reduced by restoring the function of alpha2/delta-1,” explained Rios.

She added that while the causal relationship between alpha2/delta-1 and BDNF has been established, sensitivity of it “remains unclear.” Future work will be geared at trying to gain a better understanding “at the molecular and cellular level how alpha2/delta-1 in the ventromedial hypothalamus and possibly other brain areas mediates appetite and glucose control.”

The work suggests candidate targets for “intervention strategies for obesity and glucose control disorders,” Rios explained. “The finding that alpha2/delta-1 can normalize glucose control in mice that are obese due to BDNF deficiency is particularly exciting as insulin resistance and diabetes are frequently associated with obesity in humans.”

She added that the work also is exciting because of its finding that gabapentinoid drugs, which are used to treat epilepsy and other conditions, also inhibit alpha2/delta-1 function. But “much work remains to be done to ascertain how translational our findings are to human disease,” Rios said.

“Food intake is a complex behavior regulated by equally intricate neural circuits and signaling pathways that we do not fully understand,” she said. “Feeding is driven by homeostatic processes that preserve energy levels essential for survival and by the rewarding value of palatable food in the absence of a homeostatic requirement.”

“We have established that BDNF is an essential regulator of both homeostatic and hedonic feeding in adult mice and have defined specific brain regions where its actions are required for these important effects. Moreover, we have identified alpha2/delta-1 as a downstream effector of the appetite-suppressing effects of BDNF,” she added.